Macrolide antibiotics, characterized by a large lactone ring to which are attached one or more deoxy sugars, usually cladinose and desosamine, are antimicrobial drugs that are active against aerobic and anaerobic gram positive cocci and are prescribed for the treatment of respiratory tract and soft tissue infections. The macrolides, which belong to the polyketide class of natural products, function by reversibly binding to the 505 subunit of the bacterial ribosome, blocking protein synthesis and preventing bacterial growth and reproduction. Although this action is primarily bacteriostatic, at higher concentrations, macrolides can be bactericidal. Erythromycin and the semi-synthetic derivatives azithromycin and clarithromycin are among the marketed macrolide antibiotics.
Ketolides, which are semi-synthetic derivatives of the 14-membered macrolide erythromycin A, belong to this class of drugs used to treat respiratory tract infections. These drugs are effective against macrolide-resistant bacteria because of their ability to bind to two sites on the bacterial ribosome. Telithromycin and cethromycin belong to this group of antibiotics.
Acquired bacterial resistance to macrolides occurs primarily through post-transcriptional methylation of the 23S bacterial ribosome. This results in cross-resistance to macrolides, lincosamides and streptogramins. Although rare, acquired resistance also can result from the production of drug-inactivating enzymes such as esterases or kinases, as well as the production of active ATP-dependent efflux proteins that transport macrolides out of the cell. A significant fraction of pneumococci are resistant to currently available antibiotics. Accordingly, new macrolide and ketolide antibiotics are needed, along with processes for preparing them.
In particular, international patent application publication No. WO 2004/080391, and its counterpart publication US 2006/0100164, the disclosures of which are incorporated herein by reference, describes a family of macrolide and ketolide antibiotics, including fluoroketolide antibiotics, of formula (I)
and pharmaceutically acceptable salts thereof, wherein R10, X, Y, V, W, A, B, and C are as described herein, and Me indicates methyl, and Et indicates ethyl. One notable, but non-limiting example compound of formula (I) is solithromycin, also referred to as OP-1068 and/or CEM-101. The preparation of CEM-101 and related compounds is described in WO 2009/055557, the disclosure of which is incorporated herein by reference. A starting material used in WO 2009/055557 A1 for the preparation of the macrolide antibacterial agents is clarithromycin. In the processes described therein, clarithromycin is converted into a clarithromycin derivative in which the hydroxyl groups of the sugar moieties are protected with acyl groups, such as clarithromycin dibenzoate, also known as 2′,4″-di-O-benzoyl-6-O-methylerythromycin A, to form compounds of formula (II).
and pharmaceutically acceptable salts thereof, wherein R is as described herein.
Clarithromycin is a semisynthetic antibacterial agent in which the 6-hydroxy group of erythromycin A has been converted into a 6-methoxy group to eliminate undesired interaction with the carbonyl group at the 9-position of the macrolide ring, thereby stabilizing the antibiotic. Clarithromycin has been prepared by various processes. The most widely used processes begin with erythromycin A, which is converted to its oxime and then to a protected erythromycin A 9-oxime derivative as an intermediate, and variously involve protection and deprotection of the hydroxyl and dimethyl groups of the pendant sugar moieties before and after methylation of the 6-hydroxy group of the macrolide ring (see, for example, U.S. Pat. No. 6,515,116 for a review of the reported processes; an alternative approach including protection of the desosaminyl amino group as an N-oxide is described in U.S. Pat. No. 6,809,188). For the efficient production of a clarithromycin derivative in which the hydroxyl groups of the sugar moieties are protected with acyl groups and, subsequently, of a final macrolide antibacterial agent, there is needed a preparation of the diprotected derivative from erythromycin A which avoids the protecting and deprotecting steps used in the prior methodology for the preparation of clarithromycin. Described herein are processes for the direct production from erythromycin A of clarithromycin derivatives of formula (II) in which the hydroxyl groups of the sugar moieties are protected with acyl groups with a reduced number of steps. Also described herein are processes for preparing compounds of formula (I) from compounds of formula (II).